Efficient synthesis of antiviral agent uprifosbuvir enabled by new synthetic methods

• Published in: Chemical science (Cambridge) Vol. 12; no. 26; pp. 931 - 936
• Main Authors: Klapars, Artis, Chung, John Y. L, Limanto, John, Calabria, Ralph, Campeau, Louis-Charles, Campos, Kevin R, Chen, Wenyong, Dalby, Stephen M, Davis, Tyler A, DiRocco, Daniel A, Hyde, Alan M, Kassim, Amude M, Larsen, Mona Utne, Liu, Guiquan, Maligres, Peter E, Moment, Aaron, Peng, Feng, Ruck, Rebecca T, Shevlin, Michael, Simmons, Bryon L, Song, Zhiguo Jake, Tan, Lushi, Wright, Timothy J, Zultanski, Susan L
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 07.07.2021; Royal Society of Chemistry; The Royal Society of Chemistry
• Subjects: Chemistry; Chemistry, Multidisciplinary; Ferric chloride; Hydrochlorination; Nucleotides; Oxidation; Physical Sciences; Science & Technology; Stereoselectivity; Synthesis; DESIGN; FACILE SYNTHESIS; DERIVATIVES; NUCLEOSIDES
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/d1sc01978c

An efficient route to the HCV antiviral agent uprifosbuvir was developed in 5 steps from readily available uridine in 50% overall yield. This concise synthesis was achieved by development of several synthetic methods: (1) complexation-driven selective acyl migration/oxidation; (2) BSA-mediated cyclization to anhydrouridine; (3) hydrochlorination using FeCl 3 /TMDSO; (4) dynamic stereoselective phosphoramidation using a chiral nucleophilic catalyst. The new route improves the yield of uprifosbuvir 50-fold over the previous manufacturing process and expands the tool set available for synthesis of antiviral nucleotides. An efficient route to the HCV antiviral agent uprifosbuvir was developed in 5 steps from readily available uridine in 50% overall yield.